Brain malformations are a significant cause of severe developmental disability and seizures. In many cases, less penetrant mutations in the same gene can lead to cognitive and behavior impairment without structural changes, suggesting a broadly applicable role for these genes in brain development and function. We anticipate that discovery of genes involved in these brain malformations will have direct and important implications on our understanding of mental retardation, autism and epilepsy and that this will serve as this first step toward targeted therapies. We propose to focus this grant on Aicardi syndrome (AS). This is a unique disorder of brain and eye development for which the hallmark signs are agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms. These patients also frequently have other brain malformations that include polymicrogyria, subcortical and periventricular heterotopia, cerebral asymmetry, choroid plexus papillomas and cysts, amongst others. Only females and XXY (Klinefelter) males are affected and this sporadid disorder, never occurring twice in one family (with one exception). These constellation of findings suggest that Aicardi syndrome is caused by a de novo mutation on the X chromosome. We propose to search for the causative gene using a microarray platform that will scan DNA from the X chromosome looking for deletions or duplications which may point us to the Aicardi syndrome gene. We also will pursue the cause of AS by pursuing a candidate gene approach. Moreover, many developmental disorders are found to have a broader clinical phenotype once the gene is identified. We plan to capitalize on this potential aspect of AS by sequencing the newly identified AS gene in a large cohort of individuals with agenesis of the corpus callosum, the hallmark cerebral malformation in Aicardi syndrome. PUBLIC HEALTH RELEVANCE: This discovery will ultimately have broad implications on our understanding of how the brain develops and how seizures occur in patients with malformations of brain development. This will also have important implications for our ability to understand and diagnose disorders of brain development both in affected children and in expectant mothers.